This study was conducted to assess the potential for orally administered sodium fluoride to cause developmental toxicity. The most common human exposure to NaF occurs as a result of fluoridation (1 ppm F) of municipal drinking water supplies. The lack of pertinent developmental toxicity data in the published literature prompted the initiation of this study. NaF (CAS No. 7681-49-4) was administered ad libitum in drinking water to mated CD rats (26 per group) on gestation days 6 through 15 at levels of 0, 50, 150, or 300 ppm. Control water contained less than 0.6 ppm NaF (method detection limit) and food contained an average of 12.4 ppm F (11.6 - 13.4 ppm F). The calculated doses from drinking water were 7, 18 and 27 mg NaF/kg/day (i.e., 3, 8 and 12 mg F/kg/day) for the low- through high-dose groups, respectively. Intake from food added approximately 2 mg NaF/kg/day (i.e., 1 mg F/kg/day) to the intake for each group. Animals were observed daily for clinical signs of toxicity. Food, water, and body weights were recorded for the animals in each group on gd 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20. All animals in the developmental toxicity study were killed on gd 20 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development. An additional 10 mated animals per group were subjected to the same experimental regimen but sacrificed on gd 16 for blood collection; serum samples were submitted to the sponsor for determination of serum fluoride concentration.
No maternal lethality occurred in this study. No treatment-related clinical signs of toxicity or effects on maternal body weight were observed. However, maternal weight gain was significantly reduced at 300 ppm during the first two days of exposure (gd 6 to 8), and a trend toward decreased weight gain was noted for the treatment period as a whole (gd 6 to 16). Maternal food intake (grams/kg/day) for NaF-exposed dams was generally comparable to controls, except for a significant decrease at 300 ppm from gd 8 to 10. In contrast, maternal water consumption (grams/kg/day) during exposure was significantly decreased in the animals exposed to 300 ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of decreased palatability of the 300 ppm solution. Necropsy of the maternal animals revealed no effects on kidney or liver weights. NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations. Determination of serum fluoride levels in the 10 animals per group terminated on gd 16 revealed mean levels of 0.007 ± 0.002, 0.035 ± 0.040, 0.039 ± 0.039, and 0.187 ± 0.076 ppm F at the end of the exposure period (per data provided by the NTP).
The poor palatability of the 300 ppm NaF solution in this study apparently reduced maternal water consumption. Maternal weight gain was significantly reduced from gd 6 to 8, but recovered thereafter. There was no definitive evidence of developmental toxicity at levels of sodium fluoride in drinking water as high as 300 ppm (resulting in an average exposure of 27 mg NaF/kg/day, or 12 mg F/kg/day). When rodent chow was considered as a source of F, the total intake for the high dose group was 13 mg F/kg/day. By comparison, the estimated human intake from a 1 ppm F drinking water source is approximately 0.027 mg F/kg/day, and the estimated range of intake from both food and drinking water sources for an adult human is 0.014-0.080 mg F/kg/day. Thus, the average daily intake of F from drinking water at the developmental no observed adverse effect level in this study was approximately 450 times the estimated adult human intake from a fluoridated drinking water source. Total daily intake in this study was approximately 165 times the upper estimate for human intake from food and fluids, including fluoridated water. This study established a NOAEL for maternal toxicity at 150 ppm (18 mg NaF/kg/day) and a NOAEL at 300 ppm for developmental toxicity (27 mg NaF/kg/day) administered in drinking water to pregnant CD rats during organogenesis.